Malignancies of the hematopoietic and lymphoid tissues include the lymphomas, leukemia, myeloproliferative neoplasms, plasma cell dyscrasias, histiocytic tumors, and dendritic cell neoplasms. Multiple classification schemes have been employed for these diseases over the years. The earliest classification system, namely the 2001 World Health Organization classification (WHO) classification, updated in 2008, is based on tissue architecture and the cytologic appearances of the neoplastic cells.
According to the WHO classification, there are two different types of Neoplasias arising from haematopoietic cells, namely:
1. Myeloid Neoplasias comprising Chronic Myeloproliferative Syndromes, Myelodysplasic Syndromes, an intermediate group called Chronic Myeloproliferative/Myelodysplasic syndromes and Acute Myeloid Leukaemia; and
2. Lymphoid Neoplasias comprising Hodgkin's and non-Hodgkin's Lymphomas, either B or NK/T, histiocytic and dendritic cell Neoplasias and finally Mastocytosis.
Considering this classification, it appears that the various Neoplasias arising from haematopoietic cells can be cured by different and specific treatments.
Thus, some Active Pharmaceutical Ingredients (for example Fludarabine, Melphalan, Bendamustine, Rituximab, Pralatrexate . . . ), that are recommended for the treatment of Lymphoid Neoplasias, are inefficient for treating Myeloid Neoplasias. It is therefore not possible to extrapolate the results obtained for the treatment of Lymphoid Neoplasias to the treatment of Myeloid Neoplasias.
Myeloid Neoplasias, as defined by the WHO (see above), are frequent diseases in elderly patients. Azacitidine (AZA) has been approved as an antitumor agent for the treatment of high-risk Myelodysplasic syndrome (MDS) or acute myeloid leukemia (AML) with multi-lineage dysplasia (blast count inferior at 30%) but a significant proportion of patients (approximately 40%) are refractory to this molecule. Abnormal methylation is supposed to support the effect of Azacitidine on leukemic cells but other mechanisms could also account for its additional antitumoral effect, including induction of apoptosis. The mechanisms of resistance to Azacitidine have been previously investigated in non-hematopoietic cancer cell lines.
Accordingly, a need exists for the treatment of patients which are resistant to Azacitidine treatment.
Acadesine 5′-monophospate, which is also named AICA ribotide and ZMP, has CAS RN 3031-94-5 and it is a natural occurring active metabolite of acadesine. Clinical studies in patients undergoing coronary artery bypass graft surgery demonstrate that treatment with acadesine before and during surgery can reduce early cardiac death and myocardial infarction (cf. D. T. Mangano, Journal American Medical Association 1997, vol. 277, pp. 325-332). Other patent documents relate to the use of acadesine for: preventing tissue damage due to decreased blood flow (U.S. Pat. Nos. 4,912,092, 5,817,640); treating neurodegenerative conditions (U.S. Pat. No. 5,187,162); preventing injury to the central nervous system (U.S. Pat. No. 5,236,908); treating obesity (WO 0193873); treating type diabetes (WO 0197816) and treating conditions associated with insulin resistance (WO 0209726). There are patent documents which relate to the use of acadesine 5′-monophosphate as flavouring material (U.S. Pat. No. 3,355,301), anticholestermic/anti-hyperlipemic agent (WO 9303734), antiobesity agent (WO 0193874) and antidiabetic agent (WO 0197816).
More recently, a patent has been granted for a method for treating a human patient suffering from a B-cell lymphoproliferative disorder, comprising the administration of a therapeutically effective amount of acadesine or an acadesine precursor (U.S. Pat. No. 7,560,435).
However, nothing is mentioned or suggested in the prior art in relation to the use of acadesine, acadesine 5′-monophosphate or any of their prodrugs for treating specifically Myeloid Neoplasias such as Chronic Myeloproliferative Syndromes, Myelodysplasic Syndromes, an intermediate group called Chronic Myeloproliferative/Myelodysplasic syndromes and Acute Myeloid Leukaemia.